The objectives are: (1)\determine the types and distributional frequency of human intraepithelial prostatic and urethral endocrine-paracrine (PU-EP) cells; (2)\establish an animal model (guinea pig) for PU-EP cells; (3)\analyze the relationship between PU-EP cells and prostatic pathology, in particular, dysplasia, carcinoma and nodular hyperplasia. In comparison to very similar gastro-entero-pancreatic (GEP) and broncho-pulmonary (BP) EP cells, PU-EP cells have been poorly studied. The potential significance of PU-EP cells in normal and diseased states can be extrapolated by analogy with GEP-\and BP-EP cells. These latter EP cells are of great physiologic importance, secreting biogenic amines and/or peptide hormones. Changes in EP cell number, distribution, and/or type have been related to a variety of pathologic conditions including pre-cancerous processes and dysplasia. Differentiation towards an EP cell phenotype in malignant neoplasms of the GEP and, particularly, BP regions has had a significant impact on the classification, behavior and therapy of malignant "neuroendocrine" neoplasms. Coproliferating EP cells are present 10 to 32.5% of prostatic carcinomas, and primary carcinoids and small cell carcinomas have been reported. EP cells appear to be decreased in nodular hyperplasia. Pilot studies for this grant application indicate PU-EP cells are of great potential significance since they are more numerous and diverse than generally accepted: (1)\Ultrastructural studies with morphometric analysis have demonstrated a wide range of EP cell types based primarily on secretory granule morphology. Open (cells with luminal extensions) and closed EP cell types as well as EP cells with long dendritic processes were noted; (2)\Somatostatin immunoreactivity in a few PU-EP cells was documented for the first time; and (3) Immunocytochemical (anti-NSE, anti-serotonin) and histochemical (argyrophil and argentaffin) studies were done to determine the inter-relationship of these techniques, additionally documenting the heterogeneity of EP cells and establishing the best overall methodology to further investigate the number and distribution of PU-EP cells. Many innovative techniques were specifically developed for this proposal, including large plastic sections and a direct off-the-slide "pop-off" technique for the ultrastructural studies (also used for combined ultrastructural/immunocytochemical studies). A new multipurpose stain was developed for the plastic sections. The scope and depth of thse preliminary studies will be expanded and the same general approach will be extended to the animal study and the study of pathologic tissues. (4)